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Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction (SCAR) characterized by sterile non-follicular pustules on an erythematous base that form rapidly after drug exposure. AGEP is mediated by numerous cytokines produced by drug specific T-cells that mediate neutrophilic intracorneal, subcorneal, and/or intraepidermal pustule development. Though genetic susceptibility is not fully understood, individuals with mutations in IL-36RN may be at increased risk of AGEP development. AGEP commonly presents with leukocytosis and fever in the acute pustular phase and follows a self-limited desquamative recovery phase upon removal of offending drug. Severe cases of AGEP may have multisystem organ involvement. Atypical presentations of AGEP include localized eruptions and cases with overlapping clinical and histopathological features associated with Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and generalized pustular psoriasis. Most cases of AGEP clear rapidly with systemic corticosteroids, but severe or recalcitrant cases may require other systemic therapies such as cyclosporine, and intravenous immunoglobulin.

Background/purpose Taiwan Drug-Injury Relief System (TDRS) has been implemented since 1999. More than 60% of the approved applications were associated with severe cutaneous adverse reactions (SCARs). Studies assessing SCARs using real-world evidence are very limited. TDRS offers abundant case information as a source of real-world evidence to investigate the characteristics of SCARs in Taiwan. The purpose of this study is to understand the trends and characteristics of SCARs in Taiwan. Methods Applications from Drug-Injury Relief Database (TDRD) from 1999 to 2016 were retrospectively analyzed. Results A declining trend in SCARs application was noticed after 2012, and 952 applications of SCARs were identified. The most common subtypes of SCARs were SJS/TEN (n = 455/206), DRESS (n = 228), GBFDE (n = 34) and AGEP (n = 18). The most common culprit drugs were allopurinol, carbamazepine, phenytoin, diclofenac and lamotrigine for SJS/TEN; allopurinol, phenytoin, co-trimoxazole, carbamazepine and phenobarbital for DRESS; mefenamic acid for GBFDE; non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibacterials for AGEP. The proportions of mortality cases were 28.9% for SJS/TEN; 36% for DRESS; 11.8% for GBFDE and 5.6% for AGEP. The mean latent period of SJS/TEN, DRESS, GBFDE and AGEP were 21.8 days, 29.2 days, 3.3 days and 6.7 days, respectively. Conclusions The approved drug-injury relief applications associated with SCARs were mainly SJS, TEN and DRESS. The most common culprit drugs were antiepileptics, antibacterials, antigout agents, and NSAIDs. The latent periods showed some distinct features for different types of SCARs. In light of the high mortality rate, public awareness and vigilance of SCARs are crucial for the patient safety.

PROPOSE The purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs). METHODS Frequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses. RESULTS Twenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of drug-induced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells. CONCLUSION The measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02574988.

Background Drug reactions with eosinophilia and systemic symptoms (DRESSs) and acute generalized exanthematous pustulosis (AGEP) are potentially severe cutaneous adverse drug reactions. Objective To describe the clinical findings and sensitization profiles of DRESS and AGEP patients who had been administered iodinated contrast media (ICM). Methods All adult patients in the dermatologist's French Investigators for Skin Adverse Reactions to Drugs (FISARD) network diagnosed with a DRESS or AGEP highly suspected to have been caused by an ICM were included retrospectively. Results Thirteen DRESS patients and 19 AGEP patients who had been administered ICM were included, and the median delay in DRESS and AGEP occurrence after ICM administration was short, 4 and 1 days, respectively. Five AGEP patients had systemic involvement. A high cosensitization rate (46%) was observed among the DRESS patients, mainly with beta-lactam antibiotics. Overall, 77% of our patients were sensitized to several ICM. Patch tests identified the suspected ICM for 21 cases (72%). The retrospective nature, the limited number of subjects, the absence of a control group of healthy individuals, and the lack of detailed information on previous exposure to sensitizing drugs are limitations of this study. Conclusions We report a large series of DRESSs and AGEPs related to ICM administration. Skin tests appear useful for diagnosis and potentially to identify alternative ICM.

Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are considered to be fatal and life-threatening, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs. There is an incidence of 2 to 7 cases/million per year of SJS/TEN and 1/1000 to 1/10,000 exposures to offending agents result in DRESS. However, the mortality rate of severe drug eruptions can reach up to 50%. SCARs represent a real medical emergency, and early identification and proper management are critical to survival. The common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor restriction, and cytotoxicity mechanisms. A multidisciplinary approach is required for acute management. Immediate withdrawal of potentially causative drugs and specific supportive treatment is of great importance. Immunoglobulins, systemic corticosteroids, and cyclosporine A are the most frequently used treatments for SCARs; additionally, new biologics and plasma exchange are reasonable strategies to reduce mortality. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor antagonists, mepolizumab, and omalizumab, are still under exploration. This review summarizes the clinical characteristics, risk factors, pathogenesis, and treatment strategies of severe drug eruption to guide clinical management.

We present a severe case of acute generalized exanthematous pustulosis (AGEP) secondary to trimethoprim-sulfamethoxazole complicated by non-infectious circulatory shock in a 16-year-old boy. Hemodynamic instability has been reported as a complication of AGEP in adults, but is rarely observed in pediatric patients. The patient we present demonstrated characteristic cutaneous findings of AGEP including isolated non-follicular, sterile pustules on a background of erythema with involvement at intertriginous areas and subsequently developed non-infectious circulatory shock. This case expands the spectrum of possible clinical presentations for AGEP in pediatric patients.

Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

BACKGROUND & AIMS Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are high-mortality adverse drug reactions. The risk factors and prognosis of drug-induced liver injury (DILI) concomitant with SCAR warrant clarification. We aimed to evaluate the characteristics and outcomes of DILI with SCAR. METHODS We analysed the database of a 10-year multi-centre prospective study in Taiwan from 2011 to 2020. RESULTS A total of 1415 patients with DILI were enrolled, including 81 cases combined with SJS/TEN, 74 with DRESS, 3 with AGEP and 1257 with pure DILI. Approximated 11.2% of patients had SCAR, of which allopurinol was the leading incriminated drug, followed by sulphonamides and carbamazepine. The SJS/TEN group had the highest mortality (34.6%). Jaundice, acute kidney injury and SJS/TEN were independent risk factors of mortality (odds ratio: 29.54, 4.43 and 4.86, respectively, P

On 21 January 2021, an interim analysis of a phase-3 clinical trial revealed that the investigational, recombinant-vector COVID-19 vaccine developed by Janssen Pharmaceuticals, Janssen Ad26.COV2.S, was both effective and safe in preventing moderate and severe COVID-19 in adults.1 The vaccine was approved in late February 2021 by the Food and Drug Administration, following Pfizer's BNT162b2 and Moderna's messenger RNA-1273 approval in in December 2020. All 3 vaccines are considered safe by clinical trials. Fatigue, myalgias, and headaches have been reported in up to 10% of both of the Pfizer and Moderna vaccine recipients.2 About 1.5% of the patients who received the Moderna vaccine reported hypersensitivity reactions, such as rash and urticaria, and similar morbilliform hypersensitivity rashes have been reported with the Pfizer vaccine.3,4 Johnson and Johnson's vaccine had generally mild side effects in clinical trials, including fever in 9% of volunteers.1 As the number of vaccinated individuals in the general population rises, sporadic, atypical reactions are more likely to be observed and reported. Herein, we report a case of a 74-year old man who experienced a severe cutaneous adverse reaction (SCAR) following administration of the Janssen Ad26.COV2.S vaccine. The differential diagnosis included acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and AGEP-DRESS overlap.

Background Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse drug reaction. Although acutely patients have significant morbidity and occasional systemic involvement, the clinical course is generally self-limited. To date, there has been no consensus on treatment. Objective The aim of our current study was to evaluate the clinical features, drug association, treatment, and outcomes in a cohort of patients treated in an academic medical center. Methods A retrospective review of electronic medical records over a period of 10 years from 2009 to 2018 in a single tertiary academic medical center in Singapore was performed. Forty-three medical records with probable/definite diagnosis of AGEP were identified and analyzed for statistical significance. Results Drug association was identified in 93% of cases. The most frequent drug class was antibiotics, including penicillins, cephalosporins, and vancomycin. Systemic involvement was reported in 13.9% of patients. All cases of AGEP resolved with cessation of the offending drug. There was no mortality attributed to AGEP. Treatment with systemic steroid was associated with a decreased length of hospital stay (P = .035) in patients with AGEP. Conclusion AGEP was a self-limiting adverse drug reaction that was commonly caused by antibiotics. Although there was no difference in mortality, there was a significant reduction in the length of hospitalization with systemic corticosteroid treatment compared with that of topical corticosteroid treatment of AGEP.

Acute Generalized Exanthematous Pustulosis is a rare drug-induced skin disorder that can present at any age. It is typically noted by swelling and erythema, with numerous facial and/or anogenital nonfollicular pustules that quickly disseminate. Staphylococcal scalded skin syndrome presents with erythema and swelling that similarly favor the head and intertriginous sites with subsequent bullae formation. We present a case of a four-year-old female who presented with SSSS complicated by the development of AGEP and discuss the course of her condition and treatment.

Acute generalized exanthematous pustulosis (AGEP) is a rare drug-related adverse skin reaction caused mainly by antibiotics. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat lung cancer. A 69-year-old woman with primary lung cancer (adenocarcinoma, cT3N1M1b, stage IVB) developed erythema and multiple skin pustules on her abdomen and both thighs after 7 weeks of erlotinib treatment. She also had fever and general fatigue. Histological examination of a skin biopsy specimen showed intraepidermal pustules with neutrophil and eosinophil infiltration. She was diagnosed with erlotinib-induced AGEP. AGEP resolved by erlotinib discontinuation and systemic corticosteroid treatment. The lung cancer progressed when erlotinib was discontinued, so afatinib, a second-generation EGFR-TKI, was administrated without any skin adverse effects. Afatinib successfully decreased the lung cancer, and maintained the disease stable for 1 year. Although acneiform rash was the most common skin adverse event caused by EGFR, AGEP rarely occurred. The present case also demonstrated that it is possible to switch agents, from erlotinib to afatinib, even though they have the same pharmacological effects. Although AGEP is a rare drug-related skin disorder, physicians should be aware that erlotinib may induce AGEP.

Background Hydroxychloroquine (HCQ)-induced acute generalized exanthematous pustulosis (AGEP) is poorly described in the literature. The aim of our study was to characterize the clinical, laboratory, allergological, and genetic features of HCQ-induced AGEP. Methods We conducted a retrospective study of patients with HCQ-induced AGEP diagnosed between 2011 and 2019. We performed molecular analysis to identify variations in the IL36RN gene. We also reviewed similar cases reported between 1991 and March 2020. Results Seven female patients were included. The mean age was 47 years old, and the average time from HCQ start to onset of symptoms was 40 days. All patients received topical steroids with a full resolution of the rash within an average of 39 days after HCQ withdrawal. Patch tests were performed for three patients with positive results in one case. Genetic analyses were performed for three patients, and no mutation in the IL36RN gene was identified. Conclusion The latent period and the duration for resolution of HCQ-induced AGEP may be longer than with other drugs due to the metabolic characteristics of HCQ. Mutations in the IL36RN gene were not identified in our patients.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading throughout the world. The study describes 12 patients with SARS-CoV-2 pneumonia, who developed an acute erythematous rash with nonfollicular pinhead-sized pustules, without mucosal involvement. The clinical differential diagnosis was viral rash, acute generalized exanthematous pustulosis (AGEP), or multiform erythema. computed tomography with a diagnosis of interstitial pneumonia and a respiratory tract sample positive for SARS-CoV-2 in a reverse transcriptase polymerase chain reaction assay. Patients had signs of respiratory distress and were treated with hydroxychloroquine, darunavir, ritonavir, heparin, ceftriaxone, and azithromycin. Punch biopsies showed subcorneal pustules typical of AGEP. Dermal microvascular injury and thrombosis as described in skin damage by SARS-CoV-2 infection was not observed. The direct immunofluorescence for IgG, IgA, IgM, and C3 was negative in 8 patients investigated. A polymerase chain reaction for RNA SARS-CoV-2 performed on frozen skin was negative in 5 of 6 patients. Most of our patients were treated with systemic corticosteroids. After some days (4-10), the diffuse erythema and pustules had improved. AGEP is classified as a severe cutaneous adverse reaction, provoked by drugs and acute infections. Characteristically, removal of the offending agent leads to spontaneous resolution typically in less than 15 days. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. Cutaneous adverse reactions to drugs are common and are major health problems worldwide causing considerable costs for health care systems. We suggest that in the patients with AGEP during SARS-CoV-2 pneumonia, viral infection is a risk factor for developing drug reaction.

Acute generalized exanthematous pustulosis (AGEP) is a rare, self-limiting condition. It presents with sterile skin pustules. We present a middle-aged lady with fluid nonresponsive circulatory shock and multiple organ dysfunction secondary to AGEP.

Background Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by sterile pustules on erythematous skin associated with fever and leukocytosis. The annual incidence of AGEP is estimated to be 1-5 cases per million. Cases of AGEP with oral mucosa involvement have been reported. However, reports of AGEP involving airway mucosa are limited. Case summary We report a 42-year-old woman with serious AGEP involving the airway mucosa. The patient initially developed fever and a small rash on her forehead and face. Over the next 2 d, she developed a diffuse, pustular rash over her trunk and legs. In addition, she complained of a cough with white foam-like sputum, chest tightness and dyspnea. Four days later, due to dyspnea, her mental status started to gradually deteriorate. She became more and more drowsy. Biopsies of the skin and airway mucosa suggested the diagnosis of AGEP. According to the European study of severe cutaneous adverse reactions group's scoring system, the patient scored +6 indicating a probable diagnosis of AGEP. She received intravenous methylprednisolone 120 mg/12 h for 3 d, and was eventually discharged in good condition. This patient had already experienced respiratory failure and airway mucosa involvement on admission; however, the clinicians had an insufficient understanding of AGEP. Glucocorticoid was administered for more than 10 d following onset of the disease, and her overall prognosis was satisfactory. Conclusion This case represents a rare clinical feature of AGEP and an important finding for clinicians.

Background Hydroxychloroquine is associated with myriad adverse dermatologic effects, most of which are poorly characterized by the literature, with unknown frequencies and risk factors. Objective To conduct a systematic review of the adverse dermatologic effects and predisposing factors of hydroxychloroquine toxicity. Results The review included 94 articles comprising 689 dermatologic adverse effects. A total of 21 unique dermatologic reactions were reported, most commonly drug eruption or rash (358 cases), cutaneous hyperpigmentation (116), pruritus (62), acute generalized exanthematous pustulosis (27), Stevens-Johnson syndrome or toxic epidermal necrolysis (26), hair loss (12), and stomatitis (11). Almost all underlying conditions were rheumatologic or autoimmune in nature, composed primarily of lupus erythematous (72% of all cases) and rheumatoid arthritis (14%). The range of reported mean cumulative dosages was wide, with some adverse reactions found after as little as 3 g or as much as 2500 g. Limitations Dermatologic adverse events and primary diagnoses related to the use of hydroxychloroquine may be under-reported as only case reports and clinical trials that reported at least 1 dermatologic adverse effect were included. Conclusion Although hydroxychloroquine is generally well tolerated, dermatologic adverse effects involving the skin, hair, or nails are a frequent and significant complication. Most of these reactions occurred after treatment of autoimmune conditions, often manifesting on the skin after a wide range of cumulative dosages.

Immune checkpoint inhibitors (ICPi) have emerged as a new frontier of cancer therapy. Although monoclonal antibodies to cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have revolutionized oncologic management, these agents may result in a spectrum of immune-related adverse events (irAE) of which dermatologic toxicities are among the most frequent. Prompt recognition and management of irAE is essential for dermatologists caring for the expanding population of cancer patients exposed to these drugs. Cutaneous toxicities range from mild cases to severe and life-threatening presentations that may cause significant morbidity and mortality. This review provides an overview of severe cutaneous adverse reactions (SCARs) that may develop during ICPi therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, and cutaneous eruptions associated with systemic manifestations are discussed.

Traditional and Complimentary Medicines (TCMs) can potentially cause Adverse Cutaneous Drug Reactions (ACDRs). The aim of this study was to describe the characteristics of ACDRs due to TCMs and compare with those due to conventional medicine. This was a retrospective study with 134 cases being diagnosed with ACDR at the Dermatology Clinic of a tertiary hospital in Kuala Lumpur. Most (82.1%) ACDRs were caused by conventional drugs, while 17.9% were due to TCMs. Majority (70-75%) of the ACDRs were of mild to moderate severity. The most common ACDR to TCM was Exfoliative Dermatitis (ED) and Acute Generalized Exanthematous Pustulosis (AGEP) (both 16.7%) while maculopapular rash was the most common reaction for conventional medications (25.5%). The onset of adverse reaction to TCM was about 4 weeks (60.2%) while reactions due to conventional medication was earlier (1 to 6 days, 65.4%; p

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions.

Drug hypersensitivity reactions are a diverse group of reactions mediated by the immune system after exposure to a drug. The Gell and Coombs classification divides immunologic DHRs into 4 major pathophysiologic categories based on immunologic mechanism. Anaphylaxis is a Type I hypersensitivity reaction that requires immediate recognition and treatment. Severe cutaneous adverse reactions (SCARs) are a group of dermatologic diseases that result from a Type IV hypersensitivity process and include drug reaction with eosinophilia and systemic symptom (DRESS) syndrome, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). Other types of reactions are slow to develop and do not always require rapid treatment. Emergency physicians should have a good understanding of these various types of drug hypersensitivity reactions and how to approach the patient regarding evaluation and treatment.

Acute generalized exanthematous pustulosis is a rare drug-induced eruption that is characterized by sterile non-follicular pustules arising on an often edematous diffuse erythematous background. Generalized pustular psoriasis is an acute and severe clinical form of psoriasis presenting as pustular eruption with erythematous base. Differentiating both diseases is often challenging because of their clinical and histopathological similarities. A 62-year-old woman presented with pustular eruption and fever three days after taking propyphenazone. Laboratory findings revealed leukocytosis and neutrophilia. Histopathological findings revealed a subcorneal spongiform pustule filled with neutrophils and perivascular inflammatory cell infiltration with neutrophils in the dermis. She was initially treated with systemic steroids, however, the lesions showed insignificant improvement. Treatment was then shifted to methotrexate which resulted in a dramatic clinical improvement.

Severe cutaneous adverse drug reactions are uncommon but potentially critical clinical situations demanding prompt diagnosis and treatment. We report a rare and severe case of terbinafine-induced acute generalized pustulosis. The patient was directly referred to a Burn Unit where she underwent diagnostic confirmation, systemic supportive care, and wound care treatments. Clinical and histopathological differential diagnosis of severe cutaneous adverse drug reactions is fundamental due to their significantly different management and prognosis.

Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous eruption of small, nonfollicular, sterile pustules on an edematous and erythematous background. This cutaneous eruption is frequently accompanied by systemic findings, including fever and leukocytosis. Although the vast majority of AGEP cases are associated with medications, infectious causes have been implicated.1, 2, 3 Once the underlying cause is addressed, symptoms typically resolve spontaneously within 2 weeks. Given the potential for serious comorbidities, identifying the underlying cause is imperative for successful outcome. This case report describes AGEP associated with an acute coccidioidomycosis infection.

The distribution of pustular erythema, characteristic clinical course, and pathological findings can help diagnose acute generalized exanthematous pustulosis. Clinical management should include discontinuation of the suspected drug, hydrocortisone administration, and careful follow‐up examination.

Rash, photosensitivity, erythema multiforme, and the acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown. Amiodarone, chlorpromazine, amitriptyline, and trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain fatty acids to very long-chain fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial fatty acid oxidation. Deficiency of NADPH in presence of lysosomotropic drugs promotes the synthesis of C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of ATP and NAD(P)H, e.g., by UV radiation or a potent photosensitizer can trigger likewise the collapse of the lysosomal transmembrane proton gradient resulting in lysosomal C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and acne aestivalis (Mallorca acne). The suggested model of a compartmentalized ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous fatty acid profile, and ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.

Severe cutaneous adverse reactions to medications (SCARs) include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. They are all non-immunoglobulin E mediated hypersensitivity reaction patterns, distinguished from simple cutaneous drug eruptions by immunologic pathogenesis and internal organ involvement. Herein the clinical features, diagnostic workup, and management considerations are presented for each of these major SCARs.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) are two separate pathological entities of severe cutaneous adverse reactions (SCARs) with different etiologies and treatment strategies. Diagnosis is, however, complicated by the similarity in their clinical presentation. Although there are few claims of AGEP-SJS/TEN overlap, a simultaneous true overlap of SJS/TEN and AGEP has rarely been described in the literature. Here, we report a case study of a 61-year-old female with a known allergy to sulfa drugs presenting with altered mental status, generalized weakness, and erythematous and excoriated purulent wounds. Based on initial workup and extensive consultation, the patient was diagnosed with severe sepsis secondary to diffuse purulent cellulitis, community-acquired pneumonia, and acute renal failure due to prerenal azotemia from dehydration. She was treated with several antibiotics, starting with vancomycin, piperacillin/tazobactam. Six days later, antibiotics were de-escalated to ceftriaxone and metronidazole because of the patient's improved status. The medications were withheld when the patient started developing extensive blistering on day 8. Blood cultures ruled out any bacterial etiology. Skin biopsy confirmed overlapping features of AGEP and SJS/TEN. Due to the uncontrolled progression of her rash, she was transferred to the burn unit of a higher care center. This is potentially the first histologically confirmed case of AGEP-SJS/TEN overlap in the United States. In this case study, a conclusive diagnosis would have never been made without a biopsy, especially because the condition presented clinically as SJS/TEN. We, therefore, recommend considering a potential overlap of multiple pathologies at each presentation or suspicion of a SCAR and performing an early skin biopsy in order to provide definitive diagnosis and treatment.

Background Approximately 45% of all adverse drug reactions are manifested in the skin. Although most are mild, severe cutaneous adverse reactions (SCARs) are potentially lethal. Objective To review the etiology and clinical manifestations of severe cutaneous adverse reactions (SCARs) and the demographic characteristics of patients with SCARs. Methods This study is a retrospective review of electronic medical records for patients who developed drug-induced cutaneous reactions and were treated for initial or ongoing care at a university medical center from June 4, 2008, to August 10, 2018. Search terms included Stevens-Johnson syndrome(SJS) , drug rash with eosinophilia and systemic symptoms(DRESS), acute generalized exanthematous pustulosis(AGEP), toxic epidermal necrolysis (TEN), and TEN/SJS overlap. Results Of 596 cases of drug-induced rash, 35 cases (5.9%) of SCARs were encountered (male-to-female ratio, 1.06:1.0; mean age, 48.5 years). Of those 35 cases, 32 were in white patients (91.4%). The most common manifestations were DRESS (19 [54.3%]), SJS (8 [22.8%]), AGEP (6 [17.1%]), TEN (1 [2.9%]), and overlap (1 [2.9%]). Multiple causative drugs were implicated in 14 cases, whereas a single drug was responsible in 21 cases. The most common drugs implicated were antibiotics (88.1%). The most common causative antibiotics were cephalosporins (23.7%). Most of the patients with SCARs were given triamcinolone cream and prednisone alone (18 [51.4%]), methylprednisolone alone (1 [2.9%]), methylprednisolone and prednisone combined (4 [11.4%]), methylprednisolone and prednisolone (1 [2.9%]) or prednisone and prednisolone (1 [2.9%]). Conclusion The most common SCARs were, in order, DRESS, SJS, AGEP, TEN, and overlap. The most common causative drugs were, in order, cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and fluoroquinolones.

Contrast media (CM) are an indispensable part of modern medical imaging. Adverse reactions to CM are uncommon, but frequently involve cutaneous symptoms. This two-part article reviews adverse events secondary to CM that are relevant to the practising dermatologist. Part 1 covers the classification of CM, immediate hypersensitivity reactions to CM and the newly described condition, gadolinium deposition disease. Given that there has only been two case reports to our knowledge of a delayed adverse reaction to gadolinium-based CM, this second part will focus on cutaneous delayed reactions caused by iodinated CM (ICM). Delayed hypersensitivity reactions to ICM commonly present as maculopapular exanthems, but more rarely, they can manifest as fixed drug eruptions, acute generalized exanthematous pustulosis, drug-related eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis, symmetrical drug-related intertriginous and flexural exanthema, graft-versus-host disease, vasculitis and iododerma. Delayed reactions to ICM may be underdiagnosed, as cutaneous symptoms may be attributed to oral medications, particularly if patients are on multiple drugs.

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remains incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, is highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ. Such an IL-36γ overexpression could not be observed in patients with drug-induced maculo-papular rash (MPR). In vitro, the causative drug specifically induced IL-36γ release either directly by peripheral blood monocytes from AGEP patients, or indirectly by keratinocytes in presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36γ secretion in vitro was specific for AGEP and involved the sensing of drug/albumin complex as danger signal by Toll-like receptor 4. Our results suggest that IL-36γ secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.

BACKGROUND Distinguishing acute generalized exanthematous pustulosis (AGEP) and pustular psoriasis (PS) can be challenging. Staining for plasmacytoid dendritic cells, or PDCs (producer of IFN-α/β), and MxA (an IFN-α/β inducible protein) may help discriminate these entities. METHODS Forty-three cases of AGEP and PS were compiled from two academic institutions. All cases were examined for CD123+ PDCs, eosinophils, acanthosis, papillomatosis, suprapapillary plate thinning, tortuous dilated capillaries, single necrotic keratinocytes, papillary dermal edema, vasculitis, eosinophil exocytosis, intraepidermal pustules, and subcorneal pustules. A subset of cases (n = 26) was stained for MxA. RESULTS Perivascular and intraepidermal PDCs, dilated tortuous vessels, and MxA expression in the dermal inflammatory infiltrate were significantly (P

Background: Cutaneous Adverse Drug Reaction (CADR) is a frequent problem in clinical practice since there were new drugs or drug misuse, which leads to high morbidity and mortality rate. It is often difficult to determine the offending drug only from the history. Provocation test, intradermal test or skin prick test are of significant value, but having higher risk to re-precipitate life-threatening reaction. Drug patch test (DPT) is a test, which is performed to CADR patient to determine the culprit drug. The main advantages of DPT are, it gives rarely adverse reaction and any commercialized form of drugs can be used.Methods: This is a retrospective study, aimed to analize the clinical relevance between anamnesis and DPT result in patient with history of CADR. All patient, who were performed with DPT in one year period in Dr. Soetomo General Academic Hospital Surabaya Indonesia, were evaluated in this study. Results: There were 14 patients with history of CADR, who performed DPT; consist of 7 maculopapular eruption cases, 4 Stevens-Johnson Syndrome (SJS) cases, 1 Fixed Drug Eruption (FDE) case, 1 Acute Generalized Exanthematous Pustulosis (AGEP) case and 1 Drug Reaction with Eosinophilia and Systemic Reaction (DRESS) case. There were 9 patients (64.3 %), who got positive result of DPT. The relevance between anamnesis and positive result of DPT were shown in 8 patient (88.9%) of 9 patient with positive DPT result. Conclusion: DPT has important role in identifying the culprit drug in CADR, especially when multiple drugs are involved.

Acute generalized exanthematous pustulosis (AGEP) is an acute, self-limited, widespread cutaneous eruption characterized by the development of numerous, non-follicular, sterile pustules on a background of erythematous, edematous skin. The eruption usually develops within hours to days of exposure to medications (antibiotics, antifungals, calcium channel blockers, and carbamazepine most commonly), but it has also been documented to be associated with various infections (mostly viral), spider bites, and herbal medications. After the inciting medication is removed or precipitant infection clears, the skin reaction resolves spontaneously within 1–2 weeks. The histologic hallmark of AGEP is spongiform subcorneal and/or intraepidermal pustules with marked papillary edema, polymorphous perivascular infiltrates with neutrophils, and exocytosis of some eosinophils. AGEP is immunologically mediated by a T cell-orchestrated neutrophil response through the expression of neutrophilotactic chemokines such as CXCL8.

Patient: Male, 75-year-old Final Diagnosis: Delayed IV contrast allergic reaction Symptoms: Rash Medication:— Clinical Procedure: — Specialty: Dermatology Objective: Rare co-existance of disease or pathology Background: Iodine contrast allergy can cause acute and delayed allergic reactions. Just like any other sensitivity reaction, the severity can vary from mild to moderate skin manifestations such as erythematous rash to an even more severe presentation or life-threatening event, such as angioedema and anaphylaxis. Case Report: This case report discusses a patient who presented to our institution with a diffuse complex rash 2 days after undergoing CT scan imaging with intravenous iodine contrast injection. The rash started by being maculopapular in nature. Later on, the patient developed a purpuric and petechial pattern, and eventually, an acute exanthematous pustulosis rash was noticed. Several attempts to treat the patient with intravenous corticosteroids failed. Three days after admission (5 days after the rash started), topical steroids were used in place of parenteral steroids. The rash showed remarkable improvement in a very short time. The patient was diagnosed with delayed hypersensitivity IV iodine reaction, resistant to parenteral corticosteroids. The workup of such an extensive rash and odd presentation include several laboratory tests and skin testing to be able to rule out more serious differential diagnoses. Conclusions: This case is unique as it enables us to show the importance of substituting topical management, more specifically, topical steroids that might even replace parenteral steroids, to our management in order to treat allergic reactions, especially in the presence of a rash.

Acute generalised exanthematous pustulosis (AGEP) is an unusual cutaneous reaction, most often related with a hypersensitivity reaction to commonly used drugs. It is characterized by an abrupt onset of a pustular rash within hours or days after drug exposure and usually resolves spontaneously within 1-2 weeks after drug discontinuation. Some cases associated with systemic involvement and shock have been reported. We present the case of a severe AGEP, manifesting in association with systemic involvement and haemodynamic instability resulting in shock and multiorgan dysfunction in an adult female patient diagnosed with COVID-19 infection. There were no identifiable associated drugs, and the patient was not initiated on antimalarial drugs. Our patient improved rapidly, both hemodynamically and dermatologically with no directed therapy.

Introduction Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous drug reaction. Bullous pemphigoid (BP) is an acquired autoimmune disease that might be associated with drugs. There is currently no report of tripterygium glycosides (TG)-induced AGEP-like lesions combined with BP. Case presentation A 66-year-old male with a 20-year history of psoriasis was prescribed oral TG at 1 mg/kg, three times a day, due to aggravated psoriasis. Seven days later, erythemas and blisters appeared. After another 3 days, there were two types of blisters: (1) numerous small tension blisters with a lot of neutrophils on the top similar to AGEP combined with BP; (2) a BP. After intravenous injection of methylprednisolone and gamma globulin, the lesions were controlled. Conclusion This patient developed two types of lesions，including one similar to AGEP combined BP (AGEP-like) and a BP. It's a rare drug reaciton induced by TG.

There is a dearth of robust evidence regarding coronavirus disease 2019 (COVID-19)-related coetaneous manifestations, complications and adverse treatment events. Upon review of the literature there are only a few cases reported of acute generalized exanthematous pustulosis (AGEP) in COVID‐19 patients after treatment. Therefore, we are reporting a case of a 34-year-old male not known to have any chronic illness. His severe COVID-19 infection resolved four days prior to presentation to the Emergency Department with pustular rash on erythematous base over his face, neck, upper limbs, anterior and posterior trunk including oral cavity and tounge. The rash started after he took azithromycin, oseltamivir, ribavirin, lopinavir, hydroxychloroquine, prednisolone, ceftriaxone, clindamycin, interferon (IFN) beta, and ceftazidime for COVID-19. Skin punch biopsy was done and he was diagnosed with AGEP but it was still not known if it was related to COVID-19 or a drug-induced condition. Patient was treated with betamethasone valerate 0.1% ointment and lotion, promethazine hydrochloride 25mg tablet, paracetamol 500mg tablet, calcipotriol 50mcg/g and betamethasone 0.5mg/g gel. He discharged the same day to manage at home despite not improving. In the end, we found only a few studies that describe the cutaneous manifestations of COVID-19 infection, which were mainly case reports. We can’t be sure that AGEP is a late and severe complication of COVID-19 infection. However, AGEP could be a rare adverse effect of hydroxychloroquine therapy. Improving the knowledge about a wide range of different signs and symptoms of the disease and its severity in addition to all possible adverse treatment events and complications can improve patient safety, survival rate, and quality of life.

Coronavirus disease 2019 (COVID-19) emerged in Thailand in January 2020. Thailand was the first to report a confirmed case outside China. Cutaneous eruption in COVID-19 has been reported since the disease became pandemic but limited in tropical countries such as Thailand. The aim of this study was to observe the incidence, characteristics and relation of cutaneous eruption with COVID-19 at Bamrasnaradura Infectious Diseases Institute, a referral center of emerging infectious diseases in Thailand. An observational descriptive study observed the incidence and characteristics of cutaneous eruption in 204 COVID-19-infected patients at Bamrasnaradura Infectious Diseases Institute. We report five patients, who represented six incidences of skin eruption with four characteristics: maculopapular rash (50%), acute generalized exanthematous pustulosis (16.67%), Stevens-Johnson syndrome (16.67%) and urticarial vasculitis (16.67%). Incidences of cutaneous eruption in COVID-19 at Bamrasnaradura Infectious Diseases Institute were low. Most of the incidents were associated with medication used to treat COVID-19 infection, so drug allergy cannot be excluded as a cause of the rashes. Therefore, drug allergy should always be ruled out, and skin manifestation in COVID-19-infected patients should be further observed.

Background Since the World Health Organization declared a global pandemic due to the novel coronavirus disease2019, there have been targeted efforts to establish management modalities. Hydroxychloroquine has been suggested as a possible treatment; however, it is associated with multiple adverse reactions. We report a rare case of a patient with acute generalized exanthematous pustulosis with Stevens-Johnson syndrome due to hydroxychloroquine. Acute generalized exanthematous pustulosis is characterized by acute onset of a generalized rash that is pustular and erosive in nature, affecting limbs; trunk; face; and, less often, mucosal membranes. Although rare, it is important to be mindful of this side effect because the diagnosis is often delayed, and the disease has the potential to be life-threatening. Case presentation A 68-year-old American woman presented to our hospital with a painful, rapidly spreading rash. Its morphologic features included erythema multiforme–like lesions with extensive skin sloughing in various regions of the head, neck, and trunk and mucosal involvement. Her Nikolsky sign was negative, and she had no evidence of lesions on areas of skin trauma. Four weeks prior, she had been initiated on hydroxychloroquine for a presumed diagnosis of cutaneous sarcoidosis. Three punch biopsies of the head and neck area revealed subcorneal pustules consistent with acute generalized exanthematous pustulosis. Treatment began with high doses of methylprednisolone, leading to only minimal improvement of existing areas and ongoing spread to new areas. Treatment with intravenous immunoglobulin was initiated, at which point disease stability was achieved. The patient’s rash ultimately resolved, as did her cutaneous pain and pruritus. Conclusions Among many potential adverse reactions involving hydroxychloroquine, cutaneous side effects are varied and can lead to significant morbidity or even death. The drug is currently being investigated in a multitude of trials for coronavirus disease2019 treatment, prevention, and prophylaxis after exposure to severe acute respiratory syndrome coronavirus 2. Acute generalized exanthematous pustulosis is a rare side effect of hydroxychloroquine, and even fewer cases demonstrate histologic evidence of acute generalized exanthematous pustulosis while clinically presenting with Stevens-Johnson syndrome. Patients who develop Stevens-Johnson syndrome/toxic epidermal necrolysis require best supportive care with aggressive fluid and electrolyte replacement and prevention of further breakdown of the skin barrier. With the potential of widespread hydroxychloroquine use, it is important that providers be aware of its potential severe adverse drug reactions.

A 23-year-old man with a history of end-stage renal disease was admitted to the hospital due to fever and shock, which occurred during his dialysis. One week prior, he developed an erythematous rash on his chest, face and back, associated with generalised eruption of pustules. In hospital, his status did not improve with norepinephrine and empirical broad-spectrum antibiotics. Following this, methylprednisolone was administered with remarkable improvement. Cultures revealed no infectious aetiology. Based on the morphology of the rash and a compatible skin biopsy, the diagnosis of acute generalised exanthematous pustulosis (AGEP) was established and considered the cause of his shock. The causative agent of his AGEP remained unknown. AGEP is a rare condition, most frequently associated with drug exposure. The removal of the offending agent is the treatment of choice. It can be complicated by shock in rare cases. In that scenario, systemic corticosteroids seem to improve outcomes greatly.

Patient: Male, 78-year-old Final Diagnosis: Acute generalized exanthematous pustulosis (AGEP) Symptoms: Rash Medication:— Clinical Procedure: — Specialty: Allergology • Infectious Diseases Objective: Rare disease Background: Acute generalized exanthematous pustulosis (AGEP) is a rare exanthem characterized by the abrupt onset of numerous small, non-follicular, sterile pustules arising on an erythematous base. AGEP is often associated with medications; however, it has also been connected to various viral infections including cytomegalovirus, parvo-virus B19, and Epstein-Barr virus. Coronavirus disease 2019 (COVID-19) has been associated with a variety of skin findings, including erythematous or patchy rash, urticaria, hives, blisters, petechiae, livedo reticularis, and even AGEP in a patient undergoing treatment with hydroxychloroquine. Case Report: A 78-year-old man with a past medical history of benign prostatic hyperplasia, coronary artery disease, and atrial fibrillation presented with septic shock secondary to a urinary tract infection. On day 7 of treatment with cefepime, he became febrile and developed a pustular rash and persistent hypotension without any respiratory symptoms. Subsequently, he was diagnosed with COVID-19. Skin biopsy of the rash revealed AGEP. Conclusions: AGEP is an uncommon cutaneous eruption often triggered by medications and viruses. AGEP is thought to be mediated by pro-inflammatory cells and cytokines. This report describes an unusual presentation of AGEP following treatment with cefepime for a urinary tract infection in a 78-year-old man who was found to be positive for SARS-CoV-2 infection, but was not treated with hydroxychloroquine. Although AGEP has been described in association with some viral infections, it is more commonly a drug-associated dermatosis, commonly seen during treatment with antibiotics. As in this case, AGEP usually resolves after discontinuation of the offending antibiotic.

Background Acute Generalized Exanthematous Pustulosis (AGEP)is a rare, severe skin reactionmainly caused by medications such as antibiotics, anti fungals, Calcium channel blockers and Anti malarias. Although it resolves spontaneously in most patients, systemic corticosteroids are neededin severe cases. Aims In order to determine the drug that is causing this condition, patch testing must be performed. Hydroxychloroquine is a medication that is used for the treatment of rheumatic and dermatologic conditions. And although it has been rarely seen to cause this reaction, we report a case of Hydroxychloroquine-induced (HCQ) AGEP which was confirmed by Patch testing. Patients A woman 49 years of age with an18 month history of mild, untreated Rheumatoid Arthritis experienced an acute episode of arthritis in her right elbow. Upon going to a rheumatologist, Prednisolone 5 mg BID and HCQ 200 mg daily were administered for a 30-day period. But after only 17 days of this treatment, the patient developed generalized erythema and painful pustular eruptions. Prednisolone dosage was changedto 7.5 mg per day andHCQ was discontinued one day afterthe appearance of eruptions. The diffuse erythema started improving a week after the patient's hospitalization.Considering the factthat our patient was receiving multiple potentially causative medications, patch testing was necessary to distinguish the drug responsible for this reaction. Results After the patch testing was done, HCQ-induced AGEP was confirmed. Conclusions Patch testing is the gold standard of determining the responsible drug for an AGEP reaction. It should also be kept in mind that HCQ, although rarely, can cause this condition.

A 58-year-old woman with a new diagnosis of acute myeloid leukemia underwent computed tomography (CT) of the chest and received 80 mL of intravenous radiocontrast medium (iohexol). Within 12 hours the patient had a body temperature of 40.1oC and exanthem characterized by diffuse erythema and edema

OBJECTIVE The association between human leukocyte antigen (HLA)-B*58:01 and risk of allopurinol-induced severe cutaneous adverse reactions (AIS) was observed across different populations. We explore the association between HLA-B*58:01 and AIS risk in multiethnic Malaysian population. The HLA-B*58:01 risk for different AIS clinical phenotypes and ethnicity was determined. METHODS We performed a case-control association study by genotyping the HLA-B alleles of 55 patients with AIS [11 toxic epidermal necrolysis (TEN), 21 Steven Johnson syndrome (SJS) 22 drug reaction wit eosinophilia and systemic symptoms (DRESS) and one acute generalized exanthematous pustulosis (AGEP)] and 42 allopurinol-tolerant controls (ATC). RESULTS HLA-B*58:01 was positive in 89.1 and 14.3% of the AIS and ATC study groups [odds ratio (OR) = 49.0, 95% confidence interval (CI) = 14.6-164.4, P < 0.0001)], respectively. Our data showed that 93.8% of the AIS-SJS/TEN patients and 86.4% of the AIS-DRESS patients were HLA-B*58:01 positive (AIS-SJS/TEN, OR = 90, 95% CI = 16.9-470.1, P < 0.0001 and AIS-DRESS OR = 38, 95% CI = 8.5-169.2, P < 0.0001). Stratification by ethnicity and clinical phenotypes revealed a significant increased risk between HLA-B*58:01 and Chinese-AIS patients (OR = 137.5, 95% CI = 11.3-1680.2, P < 0.0001), in particular Chinese patients with AIS-SJS/TEN phenotype (100% HLA-B*58:01 positive). HLA-B*58:01 was positive in 90.9% Chinese AIS-DRESS (P < 0.0001). Highly significant associations of HLA-B*58:01 were observed in Malay AIS-SJS/TEN (OR = 78, 95% CI = 9.8-619.9, P < 0.0001) and Malay AIS-DRESS (OR = 54, 95% CI = 6.6-442.9, P < 0.0001). Although the number of Indian-AIS patients was relatively small (n = 2), both were HLA-B*58:01 positive. CONCLUSION Our data suggest strong associations between HLA-B*58:01 and AIS in Malaysian population with Chinese and Malays ethnicity. The strong association was also observed in three different clinical phenotypes of AIS, mainly the AIS-SJS/TEN.

Background: Proton-pump inhibitors (PPI) are one of the most commonly prescribed drugs, and they are generally well tolerated. However, several immediate and delayed hypersensitivity reactions due to PPIs have been reported. Objective: To review the clinical characteristics and management of immune-mediated immediate and delayed hypersensitivity reactions to PPIs. Methods: We performed a search of a medical literature data base from January 1980 to October 2019 by using keywords that included “proton-pump inhibitors” and “hypersensitivity.” Results: Anaphylaxis is the most-common clinical presentation in patients with immediate hypersensitivity reactions to PPIs, followed by urticaria and/or angioedema. Occupational contact dermatitis, maculopapular eruption, fixed drug eruption, symmetrical drug-related intertriginous and flexural exanthema, and severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have also been reported with PPIs. Conclusion: The current knowledge and severity of the reported reactions indicated the importance of consideration of a causal relationship between hypersensitivity reactions and PPIs, and awareness of the existence of cross-reactivity among PPIs.